Is it time to target no evident disease activity (NEDA) in multiple sclerosis?

Giovannoni, Gavin; Turner, Benjamin; Gnanapavan, Sharmilee; Offiah, Curtis; Schmierer, Klaus; Marta, Mónica

doi:10.1016/j.msard.2015.04.006

Cited by 291 publications

(259 citation statements)

References 26 publications

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“…The level of control is indicated by the proportion of patients who achieve no evidence of disease activity (NEDA), a composite endpoint (no relapses, no disability progression and no MRI activity) that is often reported at 2 years in contemporary trials and has been proposed as a treatment goal in patients with RRMS 50 . Five trials of AHSCT published since 2010 have reported the proportion of patients with RRMS for whom NEDA was achieved at 2 years after transplantation 9-11,13,14,47 , and these reports have enabled comparisons with trials of other disease-modifying therapies that are either approved or close to approval 51 .…”

Section: [H2] Efficacymentioning

confidence: 99%

Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis

et al. 2017

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Autologous haematopoietic stem cell transplantation (AHSCT) is a multistep procedure that enables destruction of the immune system and its reconstitution from haematopoietic stem cells. Originally developed for the treatment of haematological malignancies, the procedure has been adapted for the treatment of severe immune-mediated disorders. Results from ~20 years of research make a compelling case for selective use of AHSCT in patients with highly active multiple sclerosis (MS), and for controlled trials. Immunological studies support the notion that AHSCT causes qualitative immune resetting, and have provided insight into the mechanisms that might underlie the powerful treatment effects that last well beyond recovery of immune cell numbers. Indeed, studies have demonstrated that AHSCT can entirely suppress MS disease activity for 4–5 years in 70–80% of patients, a rate that is higher than those achieved with any other therapies for MS. Treatment-related mortality, which was 3.6% in studies before 2005, has decreased to 0.3% in studies since 2005. Current evidence indicates that the patients who are most likely to benefit from and tolerate AHSCT are young, ambulatory and have inflammatory MS activity. Clinical trials are required to rigorously test the efficacy, safety and cost-effectiveness of AHSCT against highly active MS drugs

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Section: [H2] Efficacymentioning

confidence: 99%

Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis

et al. 2017

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“…As mentioned, NEDA-3 is a combined measure defined as absence of either a clinical relapse, or disability worsening, or radiological activity [6]. The NEDA-3 has been recently proposed as a principal aim in management of relapsing MS because it leads to better long-term outcomes .…”

Section: Outcome Measuresmentioning

confidence: 99%

“…Relapses and disability worsening assessed by the Expanded Disability Status Scale (EDSS) [4] are indeed currently accepted as main endpoints in large, phase III, randomized clinical trials [5]. More recently, the No Evidence of Disease Activity (NEDA-3) has been proposed as a new outcome measure for RRMS based on (i) absence of relapses; (ii) absence of sustained disability worsening, defined as ≥1-point increase in EDSS score confirmed 3-6 months apart; (iii) absence of radiological activity, seen on magnetic resonance imaging (MRI) as gadolinium-enhancing lesions or new/enlarged T2-hyperintense lesions [6].…”

Section: Introductionmentioning

confidence: 99%

Baseline characteristics associated with NEDA-3 status in fingolimod-treated patients with relapsing-remitting multiple sclerosis

Giuliani

Logoteta

Prosperini

et al. 2017

Mult Scler Demyelinating Disord

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Background: Fingolimod is an efficacious treatment for relapsing-remitting multiple sclerosis (RRMS) and there is class I evidence that it is superior to standard care in reducing relapse rate. However, real-world data investigating its effectiveness and potential predictors of response are still scarce. Objective: To estimate (i) the proportion of fingolimod-treated patients who achieved the no evidence of disease activity (NEDA-3) status; and (ii) to determine which baseline (i.e. at treatment start) clinical and magnetic resonance imaging (MRI) variables were associated with better outcomes. Methods: We collected clinical and MRI data of RRMS patients treated with fingolimod and followed-up for 24 months. The proportion of patients who had NEDA-3 -i.e. absence of relapses, sustained Expanded Disability Status Scale (EDSS) worsening and radiological activity on MRI -was estimated. A Cox proportional hazard model was carried out to investigate which baseline characteristics were associated with the NEDA status at follow-up. Results: We collected data of 201 patients who started fingolimod. Of them, 24 (12%) were treatment-naïve, 115 (58%) were switched after failing a self-injectable drug, and 60 (30%) switching from natalizumab. Five patients who discontinued fingolimod early (within 3 months) (bradycardia, n = 2; leukopaenia, n = 2; macular oedema, n = 1) were removed from the analysis. At follow-up, 118 (60%) patients achieved the NEDA-3 status, while 78 experienced clinical and/or MRI activity. The risk of not achieving the NEDA-3 status was associated with higher baseline EDSS score (hazard ratio [HR] = 1.18, p = 0.024) and more relapses in the 12 months prior to fingolimod start (HR = 1.61, p = 0.014). Conclusion: Our findings suggest that fingolimod may lead to a better control of the disease if started in patients with a less aggressive disease (i.e. fewer pre-treatment relapses and milder disability level), thus supporting its possible role as an early treatment for MS.

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“…In MS, the disease-activity-free (DAF) status or as more recently called, the no-evidence-of-disease activity (NEDA) status, has become a new treatment goal in daily clinical practice, and is used for decision making on treatment changes or dose adaptations for current treatments [35]. NEDA, a composite measure of disease activity, is currently defined only by 3 parameters:…”

Section: An Interim Change Of the Primary Dependent Variableuse Of Thmentioning

confidence: 99%

“…It is therefore reasonable to approach their construction in MS with comparable caution. Similarly, there are strong arguments in the recent literature against the use of NEDA as a primary outcome in clinical trials designated for regulatory approval purposes [35], even if it's recognized as an important goal for treating individual patients with relapsing disease or as a method for selecting the most appropriate therapy to move forward into confirmatory trials. In addition, the high variability of disease progression is neglected by this outcome measure.…”

Section: An Interim Change Of the Primary Dependent Variableuse Of Thmentioning

confidence: 99%

Evolving landscapes in multiple sclerosis research: adaptive designs and novel endpoints

Beelke¹,

Antonini²,

Murphy

2016

Mult Scler Demyelinating Disord

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The increasing amount of highly effective treatment options in relapsing forms of multiple sclerosis (MS) requires innovative clinical trial design strategies. These strategies may encompass the application of adaptive designs as well as the adoption of innovative primary outcome measurements. The offered advantages would include, among others, shorter study follow-up periods and reduction in the number of patients either on placebo or on non-suitable dosages of the small molecules or biological products under examination. Changing the primary endpoint during the study conduct additionally represents an option, when the primary endpoint originally is either a composite endpoint of Magnetic Resonance Imaging (MRI) and clinical variables or a unitary endpoint of clinical variables. The new outcome measurement of no-evidence-of-disease activity (NEDA) -the former disease activity free (DAF) status, might represent an attractive approach and NEDA may become a new standard for clinical trials in relapsing MS (RMS), particularly for pivotal Phase III trials, though also earlier phase trials and exploratory clinical research might benefit from this endpoint. Future studies in RMS could incorporate NEDA as a primary endpoint and utilize the adaptive design methodology in order to reduce the sample size and the duration of new therapeutic agents' clinical development.

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Is it time to target no evident disease activity (NEDA) in multiple sclerosis?

Cited by 291 publications

References 26 publications

Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis

Autologous haematopoietic stem cell transplantation for treatment of multiple sclerosis

Baseline characteristics associated with NEDA-3 status in fingolimod-treated patients with relapsing-remitting multiple sclerosis

Evolving landscapes in multiple sclerosis research: adaptive designs and novel endpoints

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